SK2362002A3 - Oral pharmaceutical forms of administration with a delayed action - Google Patents

Abstract

A partially delayed oral pharmaceutical dosage form (A) comprising tramadol (I) as active agent, (I) is at least partially in the form of a compound (I') formed in situ and having at water solubility of 50 mg/ml or less (especially 5 mg/ml or less). An independent claim is included for the preparation of (A), by mixing tramadol (I) with an acidic drug or auxiliary (II) (or its water-soluble salt) and optionally auxiliaries, wetting and formulating with application of energy.

Description

The invention relates to dosage forms for oral administration with at least partially delayed action, wherein the pharmaceutical active substance tramadol is present at least partially in the form of an in situ formed compound with a water solubility of <100 mg / ml, as well as a process for their preparation.

BACKGROUND OF THE INVENTION

The use of pharmacologically active substances in the form of delayed-release preparations represents an improvement in therapy for many of these active substances, in particular for analgesically active substances. The delay of action allows, even in the case of pharmacologically active substances with a relatively short half-life in the body, to provide long-acting formulations and, moreover, to avoid side effects and improve patient compliance through a more uniform blood count.

A delay in the action of pharmacologically active substances can be achieved e.g. by embedding the active ingredient in a delayed matrix or by applying delayed coating films. Delay of action of very well water-soluble active substances, e.g. Tramadol hydrochloride, an analgesic for the control of severe to very severe pain, with the use of coating films, is often costly, since coating films for such active ingredients often present only a poor diffusion barrier or the permeability of these coating films changes during storage (PB O'Donnell, JW McGinity) , "Mechanical Properties of Polymeric Films, Prepared from Aqueous Polymeric Dispersions in Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,", Drugs and the Pharmaceutical Science, Volume 79, ed. JW McGinity, Marcel Decker, New York, Basel, Hong Kong 1997) .

31888 / H

The production of delayed-effect coating film formulations that are applied from an aqueous dispersion requires a complex multilayer film coating process or time-consuming elevated temperature processes such as described in US 5,645,858 or US 5,580,578, US 5,681,585, US No. 5,472,712 and K. Bauer, &quot; Coated Pharmaceutical Dosage Forms &quot;, Medpharm

I

Scientific Publishers, Stuttgart 1998, B. Sutter, Dissertation, University of Dusseldorf, 1987, or F. N. Christensen, Proceed. Intern. Symp. Rel. Bioact. Mater., 17, 124 (1990).

Delays in the action of pharmaceutical active agents can also be achieved by reducing their solubility, e.g. through the formation of sparingly soluble salts (H. Sucker, Pharmazeutische Technologie, Georg Thieme Verlag, Stuttgart, New York 1991). However, the use of such sparingly soluble salts in dosage forms sometimes requires a very difficult manufacturing process for these salts.

SUMMARY OF THE INVENTION

It was therefore an object of the present invention to provide dosage forms which do not have the disadvantages of the prior art.

Surprisingly, it has now been found that this task is solved by the tramadol oral dosage form with at least partially delayed action in which the delayed action having a portion of the active ingredient is present as an in situ formed tramadol compound and other active ingredient and / or excipient with water solubility <100 mg / ml.

Preferably, the in situ water solubility of the compound formed is <50 mg / ml, particularly preferably <30 mg / ml, most preferably <10 mg / ml.

In order to produce an in situ formed compound, the active ingredient tramadol reacts preferably as a water-soluble salt, particularly preferably as tramadol hydrochloride, with a water-soluble, pharmaceutically acceptable salt of another, acidic pharmaceutical active or excipient which constitutes a compound with a water solubility of <100 mg / ml, preferably <

31888 / H mg / ml, particularly preferably < 30 mg / ml and most preferably < 10 mg / ml. These compounds are classified as poorly water-soluble compounds.

In situ formation within the meaning of the invention means that tramadol or its water-soluble salt, preferably in the manufacture of the dosage form according to the invention, is mixed with the acidic, other pharmaceutical active ingredient or excipient, or its water-soluble salt, moistened several times, alternatively, it displaces or processes by other power supply.

As the water-soluble salt of an acidic further pharmaceutical active and / or a biocompatible excipient for the preparation of an in situ formed tramadol compound, the sodium salt of diclofenac, neproxen, acetylsalicylic acid, salicylic acid, benzoic acid or saccharin, cyclamate or acesulfame is preferably used.

The delayed-acting oral dosage forms of the invention may contain the tramadol component and the other pharmaceutically active and / or excipient in any molar ratios.

In a preferred embodiment of the dosage form of the invention, the tramadol component is present in excess and is released by at least two different rates. That is, in addition to the delayed release of tramadol from the compound formed in situ, a portion of the active ingredient is released as fast as the initial dose.

In a preferred embodiment of the dosage form of the invention, the tramadol component and the acidic, other pharmaceutical active ingredient or excipient are present in equimolar amounts as the in situ formed, non-soluble compound. This achieves that. both active substances, respectively. the active substance / excipient, despite their original, resp. different solubilities in water delayed release at the same rate.

In a particularly preferred embodiment of the dosage form of the invention, tramadol hydrochloride and sodium diclofenac are converted in situ into a sparingly soluble compound with a water solubility of <0.3 mg / ml. Preferably, the ratio of the amount of tramadol to diclofenac in these dosage forms of the invention is 0.5: 1 to 4

31888 / H: 1, particularly preferably 1: 1 to 2: 1. Preferably tramadol is used in excess for the in situ reaction with diclofenac, such that the dosage forms have a rapidly releasing initial dose of tramadol and delayed release of tramadol and diclofenac at the same rate. Rapid pain relief can be achieved by combination with the immediate release of the active ingredient. Slow release of the active agent from the delayed form allows the analgesic effect to be maintained for a longer period of time.

Likewise, the delayed-release dosage forms of the invention also contain an in situ formed compound which is formed from equimolar amounts of the active ingredients tramadol and diclofenac, so that the entire amount of each active ingredient is delayed released at the same rate.

Oral administration forms of tramadol with at least partially delayed action of the invention are preferably prepared in microparticulate form, particularly preferably as granules, powder, micro-tablets or pellets. The pellets are preferably pellets produced by extrusion and spherization, preferably having a diameter of 0.1 to 3 mm.

The dosage forms of the invention may also be prepared as dragees or tablets, preferably fast disintegrating tablets. The tablets may consist of compressed pellets that disintegrate particularly rapidly.

A particular advantage of the dosage forms according to the invention is that the delayed action of tramadol is already achieved in the manufacture of the dosage form by forming an in situ compound with a water solubility of <100 mg / ml from tramadol and the other active ingredient and / or excipient without using a delayed matrix. and / or a delay coating.

The dosage forms of the invention preferably have at least one gastric juice-resistant coating that dissolves depending on the pH. Through this coating, it is achieved that insoluble substances pass through the gastric tract and the active substance (s) and / or excipient (s) reach the controlled release only in the intestinal tract. The gastric juice resistant coating may be applied from an aqueous solution or dispersion and / or from an organic

31888 / H solution. Preferably, the gastric juice-resistant coating dissolves at a pH between 5 to 7. The gastric juice-resistant coating preferably consists of shellac, a polymethacrylic acid / ethyl acrylate copolymer or a methacrylic / methyl acrylate / methyl methacrylate copolymer, methacrylic acid / methyl methacrylate copolymer, hydroxypropyl acetate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and / or cellulose acetate trimellitate.

Delay of action resulting from in-situ delay of action, and hence other modifications of the release of the active ingredient tramadol and optionally other active ingredients, can be achieved by various methods known to the person skilled in the art.

In particular, it is possible to achieve further delay in action by delaying coatings. Suitable delay coatings include water-insoluble waxes or polymers, e.g. acrylic resins, preferably poly (meth) acrylates or water-insoluble celluloses, preferably ethylcellulose. Such materials are known in the art, e.g. Bauer, Lehmann, Osterwald, Rothgang, &quot; Uberzogene Arzneiformen &quot;, Wissenschaftliche Verlaggesellschaft mbH Stuttgart, 1988, p. 69 et seq., To which reference is hereby made and which should be regarded as forming part of the description.

In addition to the water-insoluble polymers, the delay coatings may optionally also contain non-latent, preferably water-soluble polymers in an amount up to 30% by weight, such as polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, to adjust the release rate. and / or hydrophilic pore-forming agents such as sucrose, sodium chloride or mannitol and / or known plasticizers.

The dosage forms according to the invention may also advantageously contain a slightly soluble in situ formed tramadol compound also in a delayed matrix, preferably evenly distributed, due to a further delay in action.

Physiologically tolerable can be used as matrix materials

31888 / H hydrophilic materials known to those skilled in the art. Preferably, polymers, particularly preferably cellulose ether, cellulose ester and / or acrylic resins are used as hydrophilic matrix materials. Particularly preferred matrix materials are ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or derivatives thereof, such as salts, amides or esters thereof.

Also preferred are matrix materials of hydrophobic materials, such as hydrophobic polymers, waxes, fats, long chain fatty acids, fatty alcohols or the corresponding esters or ethers or mixtures thereof. Particularly preferably, mono- or diglycerides of C 12 -C 30 fatty acids and / or C 12 -C 30 fatty alcohols and / or waxes or mixtures thereof are used as hydrophobic materials.

Mixtures of said hydrophilic and hydrophobic materials can also be used as the delay material. Advantageously, the release of the active ingredients is adjusted so that the dosage forms according to the invention need to be administered at most twice, particularly preferably only once a day. The person skilled in the art is aware, based on the effect of the analgesics, at what dosage they must be used to achieve the desired effect.

Another possibility to modify the release of the active ingredient tramadol and optionally other active ingredients from the dosage forms according to the invention is to change their surface and / or use hydrophilic excipients. Surface enlargement, e.g. the use of smaller pellets results in a faster release of the active ingredient. Increasing the amount of hydrophilic excipients in the pellet core, e.g. lactose also leads to a faster release of the active substance or substances.

The dosage forms of the invention are particularly suitable for the treatment of pain or for the treatment of urinary incontinence, cough, inflammatory and / or allergic reactions, depression, drug and / or alcohol abuse, gastritis, diarrhea, cardiovascular diseases, respiratory diseases, psychiatric disorders or epilepsy.

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Another object of the invention is to provide methods for producing oral dosage forms of at least partially delayed action according to the invention, wherein tramadol or its salt and acid, another pharmaceutical active ingredient or excipient, or a water-soluble salt thereof, are mixed, moistened and processed multiple times. power supply. The mixture is preferably wetted with aqueous media, particularly preferably with water or aqueous binder solutions. The energy supply is preferably in the form of pressure and / or heat.

According to a preferred embodiment of the process according to the invention, the mixture is subjected to multiple humidification and granulation and at least one extrusion, whereupon it is optionally treated.

Preferably, after each wetting and granulating step, the mixture is extruded and / or dried.

Preferably, the mixture is pelletized after multiple wetting, granulating, extruding and / or drying, and optionally compressed into tablets after mixing with other excipients. Preferably, extrusion is performed prior to pelletization.

According to a particularly preferred embodiment of the process according to the invention, the moistened salt mixture is granulated, extruded, re-moistened and granulated, extruded and subsequently granulated. According to a further particularly preferred method, the wetted mixture is granulated, dried, rewetted and granulated, extruded and subsequently coagulated.

The pellets are preferably coated with gastric juice-resistant coatings prior to compression.

According to a particularly preferred embodiment of the process according to the invention, tramadol hydrochloride and sodium diclofenac are used to produce the in situ formed compound.

When the final treatment of the dosage form of the invention is carried out, it may be carried out by various methods known to those skilled in the art.

The dosage forms according to the invention may furthermore contain, depending on the embodiment, the usual excipients known to the person skilled in the art, and

If the dosage forms of the invention have coatings, they can be applied by conventional methods, such as e.g. by coating, spraying with solutions, dispersions or suspensions, applying a melt or powder.

Surprisingly, the dosage forms of the invention are characterized in that the release of the active ingredient tramadol and optionally other active substances from the dosage forms of the invention is not affected by changes in the release conditions within the conventional framework, such as buffer ion concentration, presence of surfactants. or by various mechanical stresses. Even after prolonged storage at an elevated temperature of up to 40 ° C, the release rates of the active ingredient (s) from the dosage forms of the invention do not change. The dosage forms obtained exhibit a storage-stable release profile.

This release of the active substances from the oral dosage forms with at least partially delayed action according to the invention takes place with a release kinetics which otherwise can only be achieved by means of a demanding matrix system. Surprisingly, it has been shown that delaying the action of the pharmaceutical active is possible without the use of conventional delay systems. In this case, the release profiles of both active substances can be adjusted by varying the size of the dosage form and incorporating soluble excipients while maintaining the overall release rate. Surprisingly, this release of both active substances from in situ produced poorly soluble tramadol diclofenac compounds, despite their very small particle size on average <5 μιτι, is just as delayed as the release of separately produced tramadol and diclofenac salts from identical dosage forms with only substantially larger particle sizes. about 20 to 100 μιτι.

Since the delay of the action of the active ingredient tramadol and optionally of the other active ingredient in the dosage forms according to the invention can be achieved without the use of further delay systems, they can be produced in a time and cost-saving manner with excellent reproducibility.

The solubility of the tramadol compounds and the corresponding other acidic pharmaceutical active ingredient or excipient was determined as follows:

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The delayed-coated pellets produced by the process of the invention containing a tramadol compound, i. (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, and the corresponding acidic pharmaceutical active or excipient, were added to the deionized water in an amount (corresponding to about 25 ° C) at 25 ° C. mg of pellets per 5 ml of deionized water) to give a solution saturated at this temperature, which was saturated after 24 hours of shaking (Vibrax device, shaking bath setting 1200 at 25 ° C). The respective saturation solubility range was estimated by preliminary experiments using each separately manufactured tramadol salt and the corresponding acidic pharmaceutical active or excipient.

After settling the saturated solution, the clear solution was pipetted and centrifuged for 5 minutes at 3500 rpm. A portion of the clear solution so obtained was transferred to an HPLC sample container, and the concentration of the tramadol compound and the corresponding acidic pharmaceutical active or excipient was determined against tramadol hydrochloride as a standard.

The release profile of the formulations produced in the examples was determined as follows:

The formulations were tested in a rotary basket apparatus (Examples 1-6) or a leaf mixer apparatus (Example 7) according to the European Pharmacopoeia at a temperature of 37 ° C (± 0.5 ° C) and a rotation speed of 100 min ^-1 or 50 min. ' ¹ . The formulation was tested for ten hours in Example 1, five hours in Example 6, and four hours in Example 5 in 900 ml enzyme-free artificial intestine (pH 7.2). In Examples 2 to 4 and 7, the formulation was first tested for two hours in 600 ml enzyme-free artificial gastric juice (pH 1.2) and then for another eight hours in 900 ml enzyme-free artificial intestine juice (pH 7.2).

The amounts of active substance released were determined by HPLC at a given time. The values and curves shown represent mean values of 3 samples each.

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DETAILED DESCRIPTION OF THE INVENTION

Hereinafter, the invention will be elucidated by means of exemplary embodiments. This explanation serves merely as an example and does not limit the general idea of the invention.

Example 1

125 g of tramadol hydrochloride, 125 g of diclofenac sodium and 250 g of microcrystalline cellulose (Avicel PH 101, FMC) were mixed homogeneously for 10 minutes in a Kenwood Chef Mixer and then, after wetting with sufficient water, granulated. The sticky lump mass of the granulate was subsequently extruded through a 1.0 mm Nica extruder (type E140). While the extrudate fiber was still extremely sticky at the start of extrusion, it was already converted to a very dry extrudate with insufficient plasticity due to subsequent spherization during extrusion. The extrudate was moistened again and granulated again. The resulting granulate was re-extruded using a Nica extruder and the wet extrudate was then sphericalized to uniformly large round pellets using a Nice Spheroniser (type S450). The pellets were dried in an oven at about 50 ° C and screened, with> 90% of the pellets in the desired sieve fraction of 800-1250 threshold.

Pellet composition:

Tramadol-HCl 50 mg

Diclofenac-Na 50 mg

Microcrystalline cellulose (Avicel PH 101, FMC) __________________ 100 mg

200 mg

The water solubility of the active ingredient tramadol from the compound formed in situ in the case of pellets produced as described above, as determined by the above method, was 0.36 mg / ml.

The release profile determined by the above method was as follows:

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Time in minutes Amount released in mg of 200 mg pellets for tramadol for diclofenac 30 10 7 120 18 15 300 26 24 600 35 33

Example 2

200 g of tramadol hydrochloride, 100 g of diclofenac sodium, 22 g of powdered succinic acid and 332 g of microcrystalline cellulose (Avicel PH 101, FMC) were mixed homogeneously in a Kenwood Chef Mixer for 10 minutes and processed into pellets analogously to Example 1.

Pellet composition:

Tramadol hydrochloride 100 mg

Diclofenac sodium 50 mg

Succinic acid, powder 11 mg

Microcrystalline cellulose (Avicel PH 101, FMC) __________________ 166 mg

327 mg

Subsequently, 500 g of sorted pellets in the fluidized bed at an inlet air temperature of 40 ° C were coated with an aqueous solution of shellac with a 5 wt. shellac, based on the weight of the pellets, resistant to gastric juices.

Coating film for 500 g pellets:

aqueous shellac solution ASL 125 (20% solids content,

Marchand and Cie)

triethylcitrate

Water

125 g

1.25 g

136.25 g

The release profile determined by the above method was as follows:

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Time in minutes Amount released in mg of 344 mg pellets for tramadol for diclofenac 120 0 0 240 61 10 480 76 25, 600 84 28

Example 3

1.25 kg tramadol hydrochloride, 1.25 kg diclofenac sodium, 1.0 kg lactose monohydrate, 0.75 kg microcrystalline cellulose (Avicel PH 101, FMC) and 0.75 kg colloidal microcrystalline cellulose (Avicel RC 591, FMC) of the Diosna (type P25) was mixed and granulated. The production of pellets was carried out analogously to Example 1 with the following changes. The sticky, wet granulate was not extruded after granulation, but was spread directly on foil-coated drying sheets and heated in an oven at 50-70 ° C for 20 minutes, avoiding moisture loss. Then the granulate was rewetted and granulated. Extrusion was performed using a Nica extruder (type E140) with a 0.8 mm extruder. Spherization of the extrudate was performed with a Nice Spheroniser (type S450). The pellets were dried in an oven, and> 90% of the pellets were 0.63 to 1.0 mm in the desired sieve fraction.

Pellet composition:

Tramadol hydrochloride 75mg

Diclofenac sodium 75mg

Lactose monohydrate 60mg

Microcrystalline cellulose (Avicel PH 101, FMC) 45mg

Colloidal microcrystalline cellulose (Avicel PH 101, FM) __________ 45mg

300 mg kg of pellets were then coated with 21 wt.% In a Kugelcoater Huttlin coating machine at an inlet air temperature of 40 ° C. Eudragit L55, based on the total weight of the pellets, from the aqueous dispersion of the following

31888 / H composition.

Coating film for 5 kg pellets:

Eudragit L30D-55 (Rom, 30% aqueous dispersion of 1: 1 polymethacrylic acid-ethyl acrylate copolymer) 3500 g

Eudragit NE30D (Röhm, 30% aqueous polyethylene acrylate-methyl methacrylate copolymer dispersion) 315 g

Triethyl citrate175 g

Talc, micronized 262.5 g

Water 3657.5 g

Capsule composition:

In each case 400 mg of coated pellets together with 46 mg of initial tramadol pellet (corresponding to 25 mg tramadol hydrochloride, 10.5 mg Avicel PH 105 and 10.5 mg l-HPC LH 31) were filled into a Zanasi E6 encapsulating machine with two pellet dosing stations. hard gelatin capsules of size 0.

The release profile, as determined above, was as follows:

Time in minutes Amount released in mg per capsule for tramadol (100 mg dose) for diclofenac (dose 75 mg) 30 25 0 120 28 0 240 56  29 480 79 50 . 600 85 56

Example 4

1.5 kg of tramadol hydrochloride, 1.0 kg of diclofenac sodium, 1.0 kg of lactose monohydrate, 0.75 kg of microcrystalline cellulose (Avicel PH 101, FMC) and 0.75 kg of colloidal microcrystalline cellulose (Avicel RC 591, FMC) equipment

Diosna (type P25) was mixed and granulated. The production of pellets was carried out

31888 / H analogously to Example 3 with the following changes. The reaction of diclofenac sodium with tramadol hydrochloride was carried out directly after the first granules in the mixer by heating the double jacket at 70 ° C for 30 minutes, with the stirrer blades being activated briefly once. After the reaction, a second granulation was carried out directly without emptying.

Pellet composition:

Tramadol hydrochloride 75 mg

Diclofenac sodium 50 mg

Lactose monohydrate50 mg

Microcrystalline cellulose (Avicel PH 101, FMC) 37.5 mg

Colloidal Microcrystalline Cellulose (Avicel PH 101, FMC) _________ 37.5 mg

250 mg kg of pellets were then coated with 22% by weight Kugelcoater Huttlin at an inlet air temperature of 40 ° C. Eudragit L55, based on the total weight of the pellets, of the aqueous dispersion having the following composition:

Coating film for 5 kg pellets:

Eudragit L30D-55 (Rohm, 30% aqueous dispersion of 1: 1 polymethacrylic acid-ethyl acrylate copolymer) 3667 g

Triethyl citrate 220 g

Talc, micronized 550 g

Water 4913.5 g

Capsule composition:

In each case 348 mg of coated pellets together with 46 mg of the initial tramadol dose pellet (corresponding to 25 mg tramadol hydrochloride, 10.5 mg Avicel PH 105 and 10.5 mg l-HPC LH31) were packed into hard pellets on a Zanasi E6 encapsulating machine with two pellet dosing stations. 0 gelatin capsules.

The release profile, as determined above, was as follows:

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Time in minutes Amount released in mg per capsule for tramadol (100 mg dose) for diclofenac (dose 75 mg) 30 27 0 120 32 0 240 78 24 I 480 94 40 600 99 45

Example 5

100 g of tramadol hydrochloride, 69 g of saccharin sodium and 169 g of microcrystalline cellulose (Avicel PH 101, FMC) were mixed homogeneously for 10 minutes in a Kenwood Chef Mixer and subsequently processed to pellets analogously to Example 1.

Pellet composition:

T ramadol hydrochloride Sodium saccharin 100 mg 69 mg Microcrystalline cellulose (Avicel PH 101, FMC) 169 mq

338 mg

The release profile, as determined above, was as follows:

Time in minutes % Of released for tramadol 30 84 120 100 240 104 J

Example 6

100 g of tramadol hydrochloride, 84 g of naproxen sodium salt and 184 g of microcrystalline cellulose (Avicel PH 101, FMC) were mixed homogeneously for 10 minutes in a Kenwood Chef Mixer and subsequently processed to pellets analogously to Example 1.

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Pellet composition:

Tramadol hydrochloride 100 mg

Naproxen sodium 84 mg

Microcrystalline cellulose (Avicel PH 101, FMC) __________________ 184 mg

368 mg

The release profile, as determined above, was as follows:

Time in minutes Amount released in mg of 344 mg pellets for tramadol for naproxen 30 72 55 120 91 88 240 101 100 300 102 102

Example 7

1.5 kg of tramadol hydrochloride, 1.0 kg of diclofenac sodium, 1.0 kg of lactose monohydrate, 0.75 kg of microcrystalline cellulose (Avicel PH 101, FMC) and 0.75 kg of colloidal microcrystalline cellulose (Avicel RC 591, FMC) of the Diosna (type P25) was mixed and processed analogously to Example 3 into pellets.

Pellet composition:

Tramadol hydrochloride 75mg

Diclofenac sodium 50mg

Lactose monohydrate 50mg

Microcrystalline cellulose (Avicel PH 101, FMC) 37.5 mg

Colloidal microcrystalline cellulose (Avicel PH 101, FM) ___________ 37.5 mg

250 mg

Subsequently, 5 kg of pellets in a Kugelcoater Huttlin coating machine were coated with 21 wt. Eudragit L55, based on the total weight of the pellets, of the aqueous dispersion having the following composition:

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Coating film for 5 kg pellets:

Eudragit L30D-55 (Röhm, 30% aqueous dispersion of 1: 1 polymethacrylic acid-ethyl acrylate copolymer) 3500 g

Eudragit FS30D (Rom, 30% aqueous copolymer dispersion

Polymethacrylic acid - methyl acrylate - methyl methacrylate) 350 g

Triethyl citrate210 g

Glycerin monostearate (Cutina GMS, Henkel) 92.4 g

Water 3134.6 g

Subsequently, 322.5 mg of pellets corresponding to a dose of 75 mg tramadol hydrochloride and 50 mg of diclofenac sodium were mixed first with 22.5 mg of cross-linked polyvinylpyrrolidone (Kollidon CL, BASF) and then with 205.6 mg of Celactose (Meggle), 25 mg. tramadol hydrochloride and 1.4 mg magnesium stearate and compressed into 7 x 14 mm longitudinal tablets with a weight of 577 mg with a break line. These disintegrated into aqueous pellets again in the aqueous medium.

The release profile, as determined above, was as follows:

Time in minutes Amount released in mg per tablet for tramadol (100 mg dose) for diclofenac (dose 75 mg) 30 25 0 120 25 0 240 65 22 360 77 31 420 81 35 600 91 42

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Claims (29)

Pharmaceutical forms of tramadol for oral administration with at least partially delayed action, characterized in that the delayed action having part of the active ingredient is present therein as an in situ formed tramadol compound and an acidic additional active ingredient and / or excipient having a water solubility < 100 mg / ml. Dosage forms according to claim 1, characterized in that the water solubility is <50 mg / ml, preferably <30 mg / ml, particularly preferably <10 mg / ml. Dosage forms according to claim 1 or 2, characterized in that tramadol is used as the water-soluble salt, preferably as tramadol hydrochloride, for the preparation of the in situ formed compound. Dosage forms according to at least one of Claims 1 to 3, characterized in that a water-soluble, pharmaceutically tolerable salt of an acidic, further pharmaceutically active substance or excipient is used for the preparation of the in situ formed compound. Dosage forms according to claim 4, characterized in that the salt used is sodium salt of diclofenac, neproxen, acetylsalicylic acid, salicylic acid, benzoic acid or saccharin, cyclamate or acesulfame. Dosage forms according to at least one of Claims 1 to 5, characterized in that the tramadol component is present in excess. Dosage forms according to claim 6, characterized in that tramadol is released by at least two different rates. Dosage forms according to at least one of Claims 1 to 5, characterized in that tramadol and the acidic pharmaceutical active substance or excipient are present in equimolar amounts as the compound formed in situ. Dosage forms according to claim 8, characterized in that tramadol a 31888 / H the acidic active ingredient or excipient is released at the same rate. Dosage forms according to at least one of Claims 4 to 9, characterized in that tramadol hydrochloride and sodium diclofenac are used as active substances for in situ preparation. Dosage forms according to claim 10, characterized in that the molar ratio of tramadol to diclofenac is 0.5: 1 to 4: 1, preferably 1: 1 to 2: 1. Dosage forms according to claim 10 or 11, characterized in that tramadol and diclofenac are released at least partially at the same rate. Dosage forms according to claim 10, characterized in that tramadol and diclofenac are present in equimolar amounts as the compound formed in situ and the entire amount of each active substance is released at the same rate. Dosage forms according to at least one of Claims 1 to 13, characterized in that they are prepared in microparticular form, preferably as granules, powder, micro-tablets or pellets, preferably as pellets, optionally filled into capsules. Dosage forms according to at least one of Claims 1 to 13, characterized in that they are prepared as dragees or tablets, preferably fast disintegrating tablets. Dosage forms according to claim 15, characterized in that the tablets consist of compressed pellets. Dosage forms according to at least one of Claims 1 to 16, characterized in that they have at least one gastric juice-resistant coating. Dosage forms according to at least one of claims 1 to 17 for the control of pain. Dosage forms according to at least one of claims 1 to 17 for the treatment of urinary incontinence. A method of making dosage forms for oral administration with at least 31888 / H according to any one of claims 1 to 19, characterized in that tramadol and the acidic pharmaceutical active ingredient and / or excipient, or their water-soluble salts and optionally further excipients are mixed, moistened and processed several times. power supply. Method according to claim 20, characterized in that the mixture is moistened with aqueous media, preferably water or aqueous binder solutions. Method according to claim 20 or 21, characterized in that the energy supply is carried out in the form of pressure and / or heat. Method according to any one of claims 20 to 22, characterized in that the mixture is subjected to multiple wetting and granulation and at least one extrusion and, optionally, then to a final treatment. Method according to any one of claims 20 to 22, characterized in that the mixture is pelletized after multiple wetting, granulating, extruding and / or optionally mixing with other excipients. The method according to any one of claims 20 to 23, characterized in that the wetted mixture is granulated, extruded, rewetted and granulated, extruded and subsequently pelletized. Method according to any one of claims 20 to 23, characterized in that the wetted mixture is granulated, dried, rewetted and granulated, extruded and subsequently pelletized. Method according to claims 20 to 26, characterized in that the pellets are compressed into tablets. 28. The method of claim 27, wherein the pellets are coated with at least one gastric juice-resistant coating prior to compression. Process according to at least one of Claims 20 to 28, characterized in that tramadol hydrochloride is used as the tramadol salt and sodium diclofenac is used as the further active ingredient.